This invention relates to a resin on which an amine oxide to be used as a catalyst in a selective oxidation reaction of an organic compound having primary hydroxyl group is adsorbed, a method for selectively oxidizing the primary hydroxyl group of an organic compound by using this resin, and a method for recovering the amine oxide used in the oxidation reaction. The present invention further relates to a method for producing uronic acid derivatives such as glucuronic acid derivatives and a method for producing glucuronic acid or glucuronolactone.
Glucuronic acid, glucuronolactone and derivatives thereof have been broadly used as drugs. To industrially synthesize glucuronic acid derivatives serving as intermediates in the synthesis of glucuronic acid and glucuronolactone, it has been a practice to selectively oxidize the primary hydroxyl group of a starting material (glucose derivative, saccharide such as starch, etc.) by using a nitrogen oxide (nitric acid, etc.) as an oxidizing agent to thereby convert the starting material into a carboxylic acid (Japanese Patent Publication for Opposition (Kokoku) 46-38781).
However, the above-described method suffers from some disadvantages. That is to say, expensive nitrogen oxide should be used therein as an oxidizing agent. In addition, it is feared that nitrogen oxide gases generated as by-products in the oxidation reaction might cause public pollution. Therefore, these gases are oxidized with air to give the original nitrogen oxide and then recovered and reused. Thus, troublesome operations and a device for the recovery of the nitrogen oxide are needed therefor.
In recent years, there have been disclosed a method for producing uronic acid derivatives by selectively oxidizing the primary hydroxyl group of a monosaccharide derivative (methyl glucoside, etc.) with 2,2,6,6-tetramethylpiperidine N-oxyl (hereinafter referred to simply as TEMPO) as an oxidizing catalyst (Tetrahedron Letters, 34(7), 1181-1184 (1993)) and a method for highly selectively oxidizing a primary alcohol by electrolytically oxidizing the primary alcohol together with an N-oxyl compound (TEMPO, etc.) (see, for example, Japanese Laid-open Patent Publication (Kokai) 2-107790). Namely, it has been indicated that amine oxides such as hindered nitroxide typified by TEMPO are useful as catalysts in selectively oxidizing primary hydroxyl group of compounds.
Also, there has been publicly known a method for producing a sugar carboxylic acid or a sugar lactone at a high yield under mild conditions by electrolyzing an liquid electrolysis mixture containing a saccharide with a ruthenium compound and a halogen salt dissolved in an electrolyte in an electrolysis cell and then collecting the sugar carboxylic acid or sugar lactone thus oxidized by the oxidation of the primary or secondary hydroxyl group of the saccharide (Japanese Patent Publication for Opposition (Kokoku) 63-46153).
However, these catalysts are generally expensive. In the industrial application, therefore, these catalysts are recovered and reused so as to cut down the production cost and reduce the waste. Since such a catalyst usually occurs as a solution in the reaction system, troublesome and inefficient procedures (azeotropic distillation with water, extraction with an organic solvent, etc.) should be performed to recover the catalyst and, moreover, a recovery device is needed therefor, thus bringing about problems in handling and cost.
Moreover, many amine oxides exert undesirable effects on the human body and, therefore, must be handled cautiously.
Accordingly, no satisfactory method has been developed so far for conveniently and efficiently oxidizing the primary hydroxyl group of an organic compound with the use of an amine oxide as a catalyst.
Under these circumstances, an object of the present invention is to provide an industrial method for selectively oxidizing the primary hydroxyl group of an organic compound wherein an amine oxide can be safely, conveniently and efficiently employed as a catalyst. Another object of the present invention is to provide a method for conveniently producing glucuronic acid or glucuronolactone, which are useful as drugs, involving the step of synthesizing an uronic acid derivative useful as an intermediate in the synthesis of glucuronic acid or glucuronolactone, while considering the environmental safeguards.
As the results of intensive studies, the present inventors have found that, in a method for producing glucuronic acid or glucuronolactone, a glucuronic acid or glucuronolactone intermediate can be produced by using an amine oxide as a catalyst in a reaction of oxidizing a saccharide without resort to any nitrogen oxide as an oxidizing agent.
The present inventors have further found that in a method for oxidizing the primary hydroxyl group of an organic compound such as a saccharide, the oxidization can be conveniently and efficiently, compared with the conventional methods, carried out by using as a catalyst a resin carrier (polyacrylic resin, polystyrene resin, polyalkylene resin, etc.) having an amine oxide adsorbed thereon and using as an oxidizing agent a halogen-containing oxidant or an electrolytically oxidized product of a halogen-containing compound. The present invention has been completed based on these findings.
Accordingly, the present invention relates to a resin on which an amine oxide is adsorbed as a catalyst to be used in the selective oxidation reaction of an organic compound having primary hydroxyl group.
The present invention further relates to a method for selectively oxidizing the primary hydroxyl group of an organic compound which comprises reacting the organic compound and a resin having an amine oxide adsorbed thereon with a halogen-containing oxidant or an electrolytically oxidized product of a halogen-containing compound. More particularly, it relates to the above-described oxidation method wherein an oxidation reaction cell for the organic compound containing the resin having the amine oxide adsorbed thereon is located separately from an electrolytic reaction cell for the halogen-containing compound. Still particularly, it relates to a method for producing an uronic acid derivative by using the above-described oxidation method.
The present invention further relates to a method for producing a glucuronic acid derivative which comprises reacting an optionally substituted saccharide and an amine oxide with an electrolytically oxidized product of a halogen-containing compound. More particularly, it relates to the above-described oxidation method wherein the resin is a polyacrylic resin, a polystyrene resin or a polyalkylene resin. Still particularly, it relates to the above oxidation method wherein the organic compound is an optionally substituted saccharide. It also relates to a method for producing a glucuronic acid derivative wherein an optionally substituted saccharide is electrolytically oxidized together with an amine oxide. The present invention furthermore relates to a method for producing a glucuronic acid derivative which comprises oxidizing by the use of a hologen-containing oxidant or electrolytically oxidizing an optionally substituted saccharide together with a resin having an amine oxide adsorbed thereon.
The term xe2x80x9corganic compoundxe2x80x9d as used in the present invention involves organic compounds having primary hydroxyl group. Examples thereof include lower and higher alcohols having primary hydroxyl group (the term xe2x80x9clowerxe2x80x9d as used herein means having 1 to 10 carbon atoms, while the term xe2x80x9chigherxe2x80x9d as used herein means having 11 or more carbon atoms), alkoxyalkanoic aicds having primary hydroxyl group, polyoxyalkylene siloxanes having primary hydroxyl group, polyoxyalkyleneamines having primary hydroxyl group, alkylpolyoxyalkylenes having primary hydroxyl group, polyoxyalkylene block polymers having primary hydroxyl group, alkylamidopolyoxyalkylenes having primary hydroxyl group, alkyl polyglucosides having primary hydroxyl group and optionally substituted saccharides having primary hydroxyl group. Preferable examples of the organic compound to be used in the present invention include lower and higher alcohols having primary hydroxyl group, alkylpolyglucosides having primary hydroxyl group and optionally substituted saccharides having primary hydroxyl group.
Examples of the lower and higher alcohols having primary hydroxyl group include methanol, ethanol, propyl alcohol, butyl alcohol, pentyl alcohol, hexyl alcohol, octyl alcohol, nonyl alcohol, decyl alcohol, lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol, heptadecyl alcohol, stearyl alcohol, nonadecyl alcohol, eicosyl alcohol, ceryl alcohol, melissyl alcohol, allyl alcohol, crotyl alcohol and propargyl alcohol.
Examples of the optionally substituted saccharides having primary hydroxyl group include monosaccharide glycosides wherein monosaccharides are substituted at the 1-position (i.e., the reducing end thereof) by lower or higher alcohols, derivatives wherein monosaccharides are protected at the reducing end by hemiacetals with lower alcohols, derivatives wherein the reducing end and the hydroxyl group at the 2-position form lower ketal or aromatic ketal rings, oligosaccharides wherein a constituting saccharide is substituted at the 1-position by another constituting saccharide, and glycosides wherein the monosaccharides form glycosides with lower alcohols at the 1-position. More particularly speaking, examples thereof include methyl-xcex1-D-glucopyranoside, methyl-xcex2-D-glucopyranoside, isopropyl-xcex1-D-glucopyranoside, isopropyl-xcex2-D-glucopyranoside, benzyl-xcex1-D-glucopyranoside, benzyl-xcex2-D-glucopyranoside, glucose diethylacetal, 1,2-O-isopropylidene glucose, 1,2-cyclohexylidene glucose, 1,2-O-benzylidene glucose, etc.
Examples of the alkyl polyglucosides having primary hydroxyl group include maltose, methyl maltoside, benzyl maltoside, cellobiose, methyl cellobioside, maltotriose, cyclodextrins, starch semi-hydrolysates, sucrose, lactose, etc.
The term xe2x80x9camine oxidexe2x80x9d as used herein involves secondary amine N-oxyls, tertiary amine N-oxides and oxonium salts thereof which are usable as a catalyst in a reaction of oxidizing an organic compound.
Examples of the secondary amine N-oxyls include di-t-butylamine N-oxyl, di-s-butylamine N-oxyl, 2,2,6,6-tetramethylpiperidine N-oxyl and 4-substituted derivatives thereof, 2,2,5,5-tetramethylpyrrolidine N-oxyl, dicyclohexylamine N-oxyl, etc. Examples of the tertiary amine N-oxides include trimethylamine N-oxide, N-methylmorpholine N-oxide, 2,6-dimethylpyridine N-oxide, 2,5-dimethyopyrrole N-oxide, etc.
As the amine oxide to be used in the present invention, it is particularly preferable to employ 2,2,6,6-tetramethylpiperidine N-oxyl and 4-substitued derivatives thereof including 4-acetamino-2,2,6,6-tetramethylpiperidine N-oxyl, 4-hydroxy-2,2,6,6-tetramethylpiperidine N-oxyl and 4-benzoyloxy-2,2,6,6-tetramethylpiperidine N-oxyl, 2,2,5,5-tetramethylpyrrolidine N-oxyl, dicyclohexylamine N-oxyl and 2,6-dimethylpyridine N-oxide.
The resin to be used in the present invention may be an arbitrary one, so long as it can adsorb the amine oxide and is not decomposed by the halogen oxide employed as the oxidizing agent or the base added thereto. For example, use can be made therefor of polystyrene resins, polyacrylic resins, methacrylic resins, polyalkylene resins (polyethylene resins, polypropylene resins, etc.), dextran, cellulose, agarose and hydrophilic vinyl polymers. It is preferable to use a polystyrene resin or a polyacrylic resin therefor. More particularly speaking, it is preferable to use a polyacrylamide resin, a polyacrylate resin or a polystyrene resin having an aromatic ring substituted by a halogen (fluorine, chlorine, bromine or iodine).
As the resin to be used in the present invention, an adequate one may be selected depending on the molecular weight and physical properties (polarity, etc.) of the amine oxide which is to be adsorbed as a catalyst. The specific surface area of the resin to be used in the present invention ranges preferably from 1 to 1,000 m2/g, still preferably from 20 to 800 m2/g. The pore volume of the resin to be used in the present invention ranges preferably from 0.1 to 2 ml/g, still preferably from 0.5 to 1.2 ml/g.
The shape of the resin to be used in the present invention is not particularly restricted. It may be one which can be easily dispersed in a solution by agitating, one which can be separated from the reaction system by a simple filtration procedure after the completion of the reaction, or one which can be packed into a container such as a column (e.g., beads).
Examples of marketed polyacrylic resin products usable as the resin to be used in the present invention include xe2x80x9cDiaionxe2x80x9d HP2MG (Mitsubishi Chemical Industries), xe2x80x9cAmberlitexe2x80x9d XAD-7 (Rohm and Haas), xe2x80x9cAmberlitexe2x80x9d XAD-8 (Rohm and Haas), etc. Examples of marketed polystyrene resin products usable therefor include xe2x80x9cDiaionxe2x80x9d HP20 (Mitsubishi Chemical Industries), xe2x80x9cDiaionxe2x80x9d HP21 (Mitsubishi Chemical Industries), xe2x80x9cSepabeadsxe2x80x9d SP207 (Mitsubishi Chemical Industries), xe2x80x9cSepabeadsxe2x80x9d SP825 (Mitsubishi Chemical Industries), xe2x80x9cSepabeadsxe2x80x9d SP-850 (Mitsubishi Chemical Industries), xe2x80x9cAmberlitexe2x80x9d XAD-1 (Rohm and Haas), xe2x80x9cAmberlitexe2x80x9d XAD-2 (Rohm and Haas), xe2x80x9cAmberlitexe2x80x9d XAD-4 (Rohm and Haas), xe2x80x9cAmberlitexe2x80x9d XAD-2000 (Rohm and Haas), etc.
The term xe2x80x9chalogen-containing compoundxe2x80x9d as used herein involves compounds capable of forming halogen (i.e., fluorine, chlorine, bromine or iodine) ions in water. Preferable examples thereof include those capable of forming a chlorine or bromine ion. More particularly speaking, use can be made therefor of sodium chloride, potassium chloride, sodium bromide, potassium bromide, calcium chloride or calcium bromide. Preferable examples thereof include sodium chloride, potassium chloride, sodium bromide and potassium bromide.
The terms xe2x80x9chalogen-containing oxidantxe2x80x9d and xe2x80x9celectrolytically oxidized product of a halogen-containing compoundxe2x80x9d as used herein mean compounds capable of forming halogenic acid ions, i.e., halogen ion oxides such as chlorate, bromate, iodate, chlorite, bromite, iodite, hypochlorite, hypobromite or hypoiodite. Preferable examples thereof include compounds capable of forming hypochlorite and hypobromite ions. More particularly speaking, it is preferable to use sodium chlorate, sodium chlorite, sodium hypochlorite, potassium chlorate, potassium chlorite, potassium hypochlorite, calcium chlorate, calcium chlorite, calcium hypochlorite, sodium bromate, sodium bromite, sodium hypobromite potassium bromate, potassium bromite, potassium hypobromite, calcium bromate, calcium bromite, calcium hypobromite, sodium iodate, sodium iodite, sodium hypoiodite, potassium iodate, potassium iodite, potassium hypolodite, calcium iodate, calcium iodite, calcium hypoiodite, etc. It is preferable to use sodium hypochlorite, potassium hypochlorite, sodium hypobromite or potassium hypobromite.
The term xe2x80x9curonic acid derivativexe2x80x9d as used herein involves glycosides of monosaccharides having a hexose protected at the reducing group at the 1-position and oligosaccharides and polysaccharides having these monosaccharides as the constituents thereof wherein the primary hydroxyl group has been converted into a carboxyl group. Particular examples thereof include glucuronic acid derivatives having glucuronic acid as the constituting monosaccharide, mannuronic acid derivatives having mannuronic acid as the constituting monosaccharide and galacturonic acid derivatives having galacturoninc acid as the constituting monosaccharide.
As the xe2x80x9cglucuronic acid derivativexe2x80x9d to be used in the present invention, it is preferable to select, from among glucuronic acid derivatives having glucuronic acid as the constituting monosaccharide, those capable of forming glucuronic acid or glucuronolactone (i.e., the lactone derivative of glucuronic acid) by hydrolysis. Particular examples thereof include methyl-xcex1-glucopyranosiduronic acid, methyl-xcex2-glucopyranosiduronic acid, isopropyl-xcex1-glucopyranosiduronic acid, isopropyl-xcex2-glucopyranosiduronic acid, 1,2,-O-isopropylidene glucuronolactone, sucrose 6-carboxylic acid, cyclodextrin 6-carboxylic acid and oxidized starch. Among all, it is preferable to use methyl-xcex1-glucopyranosiduronic acid, isopropyl-xcex1-glucopyranosiduronic acid or isopropyl-xcex2-glucopyranoside therefor.